1. Field of Invention(s)
The inventions relate to novel hydrophilic materials which are useful in the fabrication of novel hydrophilic chambers, to said novel hydrophilic chambers, to novel devices comprised of said hydrophilic chambers containing biologically active tissues, and to novel methods for their preparation and to their uses. In various aspects the inventions relate to the treatment of endocrine deficiencies or hypoendocrine syndromes using said chambers and said devices.
2. Prior Art
Biologically active tissue of an animal or human is subject to various disorders and diseases which result in the under production or non-production of biologically active hormones, secretants and products. Other modes of treatment for such tissue deficiencies include bolus injections, whole organ transplants, and mechanical devices for the delivery of hormones or other physiologically important species. Certain problems and drawbacks are associated with each of these treatments to the disease clinically manifested by the deficient state, e.g., endocrine deficiency or hypoendocrine syndrome.
For normal physiological function, the body has a continuous feedback system which is self-regulating. In addition, many biological species work in a concerted fashion to produce the required effect. The practice of bolus injections ignores this fine balance and current technology is not capable of producing reliable implantable glucose sensors, and there are additional intrinsic reliability problems with any mechanical system.
Whole organ transplantation presents special problems of its own. Normally one must resort to some form of immunosuppression which invariably produces many undesirable side effects. Also, the availability of implantable whole organs is very limited.
To illustrate the potential clinical significance of a device for the implantation of biologically active tissue, a detailed description of one of the most widespread endocrine deficiencies, diabetes, is given. No suitable treatment for diabetes was available until the discovery of insulin in 1921. Insulin treatment prevented death from diabetic coma and controlled overt symptoms of the disease, and was mistakenly believed to be a "cure" for diabetes. The prolonged life span made possible by insulin, however, revealed new complications associated with diabetes, such as blindness, kidney disease and cardiovascular disease.
Efforts to cope with diabetes have failed to prevent the disease from increasing. Few substantial improvements in therapy have occurred since the discovery of insulin more than 50 years ago. There is a need not only to prevent and cure diabetes, but also to develop better methods for treating the disease and its complications, which affect virtually every system of the body.
Added to the physical problems of diabetes are the psychosocial and economic effects on the diabetic patient and his family. Persons with diabetes, faced with the prospect of a lifelong disease, possible blindness, and a decreased life expectancy, are understandably plagued by fear and in need of education and counseling. Because the disease requires daily attention, persons with diabetes need instruction in self-therapy, how to administer their own insulin, how to regulate their diet, how to balance physical activity with diet and insulin, and how to explain their disease to others.
Amelioration of diabetes by implantation of a whole organ has been, in general, unsuccessful. Consequently, there has been increased interest in recent years in transplantation of isolated pancreatic islet cells. Successful amelioration of the diabetic state in experimental diabetic animals by transplantation of islet cells has been demonstrated in recent years. Nevertheless, most of these demonstrations have employed isografts or autografts and, therefore, have circumvented the problem of immunosuppression. Those investigators who have addressed the immunological problem have, in general, resorted either to drug immunosuppression, host irradiation, or encapsulation of the islets in diffusion chambers for immunological protection. Drug immunosuppression and host irradiation, however, have not proved successful in the long run, and their dangerous systemic side effects make them prohibitive for consideration in young diabetics.
Diffusion chambers of cellulosic or polycarbonate materials containing islet cells have been planted in animals. However, the resulting device, e.g., chamber and cells, generally remains effective for limited periods of time because the body encapsulates the device with fibrous material blocking the passage of insulin, nutrients, and/or waste products.
Gates, R. J., et al.: Reversal of Streptozatocin Induced Diabetes In Rats By Intraperitoneal Implantation of Encapsulated Neonatal Rabbit Pancreatic Tissue, (1977) LANCET II: 1257-1259, discloses the implantation of diced rabbit neonatal pancreas, encased in Nucleopore chambers (0.4 .mu.m pore rating), which reversed streptozotocin-induced diabetes in rats. It is reported that no rejection reactions were observed after six weeks.
The literature is replete with studies demonstrating the diffusion of non-protein, low molecular weight species across hydrogel films.
U.S. Pat. No. 4,064,086 discloses hydrogels formed from certain thermoplastic hydrophilic polymers condensed from a spirolactone and a difunctional compound. Formation polymerization can be carried out in the presence of various useful additives. The additive can be a nonreactive biologically active agent, such as, a therapeutic drug. U.S. Pat. No. 4,056,496 discloses a hydrogel prepared from a hydrophilic acrylate monomer. The hydrogels can be impregnated with a solution containing a drug. U.S. Pat. No. 3,577,512 discloses an oral sustained release dosage form composed of a finely divided therapeutically active agent (e.g., a hormone) and a water insoluble hydrophilic acrylate or methacrylate polymer. U.S. Pat. No. 3,896,806 discloses an implant for directed infusion of active substances, such as, a drug. The implant consists of a hollow body with one wall formed by a thin permeable membrane and with a chamber inside the body, which chamber is connected at least by one channel with the outside space. This enables practically undirectional diffusion of the active substance directly to the affected tissue and ability to maintain or arbitrarily change the concentration and type of the active agent.
U.S. Pat. No. 3,975,350 discloses an implantable polyurethane carrier system containing an active agent, such as medicinal agents, enzymes and antioxidants. The carrier system can be a hydrogel which provides a leachable matrix for leaching out the active agent by body fluids. U.S. Pat. No. 3,857,932 discloses an implantable dry composition of a therapeutically active material and a water insoluble hydrophilic acrylate polymer. The active material can be a number of things such as antibiotics, hormones and vitamins. U.S. Pat. No. 3,551,556 discloses a system whereby drugs are released gradually to a living organism after oral ingestion, implantation, or external application to the skin or a mucous membrane through a layer of a non-inorganic, neutral hydrogel of a polymer of ethylene glycol methacrylate or similar monomer cross-linked sufficiently to make the polymer insoluble in all body liquids. The drug may be distributed in the monomer mixture prior to polymerization or enveloped by an outer coating of the hydrogel. The term biologically active substances therein is not extended to biologically active living cells or tissue.
U.S. Pat. No. 3,885,078 discloses preparing a spongy hydrogel made by polymerizing ethylene glycol monomethacrylate (or the like) in the presence of a small amount of a cross-linking agent and more than 60 percent of water. A laminate thereof can be used as a dressing for burn wounds after it has been provided with fine holes (e.g., by means of a sharp brush)--the fine holes allow removal of the exudate, but prevent access to bacteria. U.S. Pat. No. 3,825,458 is based on the same patent application.
U.S. Pat. No. 3,499,862 discloses that sparingly cross-linked polymers reach osmotic equilibrium with water or aqueous liquids at a water content of 40 percent or less. If the polymer contains less than 40 percent water, it will absorb water from an ambient aqueous medium and its volume will increase by swelling.
U.S. Pat. No. 3,767,790 discloses dosages of microorganisms are entrapped in a hydrophilic acrylate or methacrylate to provide controlled release or quick release or to provide a regulated time of contact with an environment on which the microorganisms can act. The disclosure is limited to microorganisms, such as, bacteria, which is stated to be advantageous over the type of scheme where leachable nutrients are entrapped in a polymer. U.S. Pat. No. 3,860,490 is based on a division of such patent.
U.S. Pat. No. 3,963,685 discloses that water-insoluble, methanol-soluble, hydrophilic polymers such as polymers of 2-hydroxyethyl methacrylate can be prepared by limiting the amount of crosslinking agent such as ethylene glycol dimethacrylate to 0.035 weight percent, or less, based on the weight of monomers. The patentee further establishes in a series of experiments that this methanol-solubility characteristic of the polymer is converted to methanol-insolubility by using from 0.05 to 0.088 weight percent crosslinking agent; see Table 5 of U.S. Pat. No. 3,963,685. The patentee neither contemplates the preparation nor does he disclose the novel chambers and novel devices of the inventions contemplated herein. Additionally, data presented herein, particularly Example 8 and SEM photographs (FIGS. 13-16) of patentee's hydrophilic polymer vis-a-vis applicants' hydrophilic polymer, establish significant differences discussed hereinafter to render the applicants' hydrophilic polymers patentable thereover.
Prehn, R. I., et al.: The Diffusion-Chamber Technique Applied To A Study Of the Nature of Homograft Resistance. (1954) J.N.C.I. 15:509-517, discloses experiments with tumor cells in an implant in the peritoneal cavity of mice.
Further see U.S. Pat. Nos. 3,428,043, 3,574,826, 3,567,660, 3,641,237, 3,660,071, 3,660,563, 3,670,073, 3,681,089, 3,681,248, 3,689,634, 3,699,089, 3,737,521, 3,765,414, 3,772,215, 3,818,894, 3,861,416, 3,862,452, 3,881,026, 3,982,537, 3,995,635, 4,030,499, 4,069,307, 4,081,402, 4,140,121 and 4,140,122.
Attention is also drawn to the following references:
Abrahams, R. A., et al.: Blood Compatible Coatings of Hydron Hydrophilic Polymers, (1975) Polymer News 3: 11-19.
Abrahams, R, A., et al.: Biocompatible Implants for The Sustained Zero-order Release of Narcotic Antiseptic. (1975) J. Biomed. Mats. 9: 355-366.
Langer, R., et al.: Polymers For The Sustained Release Of Proteins And Other Macromolecules. (1976) Nature Vol. 263, No. 5580: 707-800.
Dsobnik, J., et al.: Diffusion of Antitumor drugs Through Membranes From Hydrophilic Methacrylate Gels. (1974) J. Biomed. Mater. Res. 8: 45-51.
Zentner, G. M., et al.: Progestin Permeation Through Polymer Membranes II: Diffusion Studies On Hydrogel Membranes. (1978) J. Pharm. Sci. Vol. 67, No. 10: 1352-1355.
Holdon, R. A., et al.: Structure and Permeability of Porous Films of Polyhydroxyethyl Methacrylate. (1972) Br. Polym. J. 4: 491-501.
Algire, G. H., et al.: Recent Developments in the Transparent-Chamber Technique as Adapted to the Mouse. (1949) J.N.C.I. 10: 225-253.